1. Field of the Invention
The subject invention generally relates to preventing cell injury and death and, more particularly, to administering ionizable congeners of aromatic and aliphatic alcohols to animals for therapeutic and prophylactic purposes including preventing carcinogenesis.
2. Description of the Prior Art
In general terms, cell injury is characterized by changes in cellular metabolic performance and alterations in cellular structure. Cell injury is assumed to be reversible upon termination of the insult or by the addition of a cytoprotective agent during the early stages; however, if the insult continues unchecked, the cell becomes non-functional and unrecoverable. Irreversible cell injury equates to cell death.
The pathological and physiological consequences of cell injury affect the functional and structural integrity of tissue and organ systems as well as the organism itself. Both endogenous and exogenous "insults" can cause cell injury. Endogenous insults are cellular factors, and they include the formation of reactive intermediates (i.e., oxygen free radicals generated during cellular electron transport processes), reduction in oxygen tension (i.e., in ischemia), and stimulation of inflammatory and immune processes. Exogenous insults are environmental factors, and they include exposure to drugs or chemicals, physical stimuli (i.e., radiation), or biological hazards (i.e., viruses).
Recent studies suggest that endogenous and exogenous insults cause cellular injury predominantly by generating reactive intermediates such as free radicals. The majority of reactive intermediates formed during cell or tissue injury are oxygen free radicals such as superoxide anion, hydroxyl free radical, or singlet oxygen and reactive oxygen containing compounds such as hydrogen peroxide. Once formed, both chemical and oxygen derived free radicals can react with a variety of cellular constituents including proteins, nucleic acids, and membrane lipids.
Cells contain endogenous protective systems to ensure viability and promote metabolic performance. For example, alpha-tocopherol is a free radical scavenger present in cellular membranes which binds free radicals in the cell. Alpha-tocopherol, which is often referred to as Vitamin E, is believed to protect against a variety of pathological processes including carcinogenesis, aging, chemical-induced toxicity, radiation-induced toxicity, ischemia-induced damage, and atherosclerosis. Alphatocopherol is not synthesized in mammalian cells, but rather, is derived from exogenous sources. Because unesterfied alpha-tocopherol is readily degraded when exposed to oxygen in the air, an ester derivative of alpha-tocopherol (alpha-tocopheryl acetate), is commonly used to provide a stable dosage form of alpha-tocopherol. Cellular esterases release the alpha-tocopherol in the cell by degrading the ester linkage.
The administration of succinate in high concentrations can protect cells from a variety of toxic insults. Providing the cell with additional quantities of succinate, a substrate in the tricarboxylic acid cycle, can result in energy production from oxidative phosphorylation and glycolysis which produce adenosine triphosphate (ATP) and result in glucose production from gluconeogenesis Kondrashova et al., Biochem. Biophys. Res. Comm. 109:376 (1982), reported that the addition of 6 mM succinate to isolated rat liver mitochondria increased the Ca.sup.2+ capacity and Ca.sup.2+ retention of mitochondria five to seven fold. Cellular absorption and accumulation of succinate is limited by the polarity of the succinate molecule except in the kidney where a transport system exists. Rognstad, Arch. Biochem. Biophys. 230:605, (1984), has shown the cellular uptake of succinate can be advanced by administering a more lipophilic form of succinate (i.e., methyl ester of succinate). Cellular esterases will release the succinate moiety by degrading the ester linkage. Millimolar concentrations of succinate or methyl ester succinate are required to stimulate gluconeogenesis or ATP production to provide cytoprotection (See, Rognstad, Arch. Biochem. Biophvs. 230:605 (1984) and Sanders, Proc. Soc. Exp. Biol. Med. 130:1021, (1969)).